Role of lysophosphatidic acid receptor LPA2 in the development of allergic airway inflammation in a murine model of asthma

Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
Respiratory research (Impact Factor: 3.09). 11/2009; 10(1):114. DOI: 10.1186/1465-9921-10-114
Source: PubMed


Lysophosphatidic acid (LPA) plays a critical role in airway inflammation through G protein-coupled LPA receptors (LPA1-3). We have demonstrated that LPA induced cytokine and lipid mediator release in human bronchial epithelial cells. Here we provide evidence for the role of LPA and LPA receptors in Th2-dominant airway inflammation.
Wild type, LPA1 heterozygous knockout mice (LPA1+/-), and LPA2 heterozygous knockout mice (LPA2+/-) were sensitized with inactivated Schistosoma mansoni eggs and local antigenic challenge with Schistosoma mansoni soluble egg Ag (SEA) in the lungs. Bronchoalveolar larvage (BAL) fluids and lung tissues were collected for analysis of inflammatory responses. Further, tracheal epithelial cells were isolated and challenged with LPA.
BAL fluids from Schistosoma mansoni egg-sensitized and challenged wild type mice (4 days of challenge) showed increase of LPA level (approximately 2.8 fold), compared to control mice. LPA2+/- mice, but not LPA1+/- mice, exposed to Schistosoma mansoni egg revealed significantly reduced cell numbers and eosinophils in BAL fluids, compared to challenged wild type mice. Both LPA2+/- and LPA1+/- mice showed decreases in bronchial goblet cells. LPA2+/- mice, but not LPA1+/- mice showed the decreases in prostaglandin E2 (PGE2) and LPA levels in BAL fluids after SEA challenge. The PGE2 production by LPA was reduced in isolated tracheal epithelial cells from LPA2+/- mice. These results suggest that LPA and LPA receptors are involved in Schistosoma mansoni egg-mediated inflammation and further studies are proposed to understand the role of LPA and LPA receptors in the inflammatory process.

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Available from: Evgeny V Berdyshev, Oct 02, 2015
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    • "Lysophosphatidic acid (LPA) is a prominent lipid component of serum that has pleiotropic effects in cell development, inflammation, and cancer [4], [5], [6]. The biosynthesis of LPA involves either the sequential action of secretory phospholipase A (sPLA) and lysophospholipase D or phospholipase D followed by cytosolic PLA, and can also be achieved by phosphorylation of monoacylglycerol (MAG) by MAG kinases [7]. "
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    ABSTRACT: Lysophosphatidic acid (LPA) is a bioactive lipid inducing proliferation, differentiation as well as cytokine release by mast cells through G-protein coupled receptors. Recently GPR92/LPA5 was identified as an LPA receptor highly expressed by cells of the immune system, which prompted us to investigate its presence and influence on mast cells. Transcript analysis using quantitative real-time PCR revealed that LPA5 is the most prevalent LPA-receptor in human mast cells. Reduction of LPA5 levels using shRNA reduced calcium flux and abolished MIP-1β release in response to LPA. LPA5 is a bona fide LPA receptor on human mast cells responsible for the majority of LPA induced MIP-1β release.
    PLoS ONE 03/2011; 6(3):e18192. DOI:10.1371/journal.pone.0018192 · 3.23 Impact Factor
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    • "This receptor interacts with heterotrimeric G proteins G i/o , G 11/q , and G 12/13. Constitutive receptor loss in mice produces a grossly normal phenotype; however, this receptor contributes to LPA signaling in the developing nervous system (Kingsbury et al., 2003; Dubin et al., 2010), synaptic functions in the adult CNS (Trimbuch et al., 2009), and effects on the male reproductive system (Ye et al., 2008), on the basis of the combined deletion of multiple LPA receptors, and has also been linked to some forms of cancer (Lin et al., 2009) and lung function in asthma (Zhao et al., 2009). 3. LPA 3 . "
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    ABSTRACT: Lysophospholipids are cell membrane-derived lipids that include both glycerophospholipids such as lysophosphatidic acid (LPA) and sphingoid lipids such as sphingosine 1-phosphate (S1P). These and related molecules can function in vertebrates as extracellular signals by binding and activating G protein-coupled receptors. There are currently five LPA receptors, along with a proposed sixth (LPA₁-LPA₆), and five S1P receptors (S1P₁-S1P₅). A remarkably diverse biology and pathophysiology has emerged since the last review, driven by cloned receptors and targeted gene deletion ("knockout") studies in mice, which implicate receptor-mediated lysophospholipid signaling in most organ systems and multiple disease processes. The entry of various lysophospholipid receptor modulatory compounds into humans through clinical trials is ongoing and may lead to new medicines that are based on this signaling system. This review incorporates IUPHAR Nomenclature Committee guidelines in updating the nomenclature for lysophospholipid receptors (
    Pharmacological reviews 12/2010; 62(4):579-87. DOI:10.1124/pr.110.003111 · 17.10 Impact Factor
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    ABSTRACT: Endothelial cells play an important role in the recruitment of immune cells to a disease locus through the induced expression of chemokines and cell adhesion molecules (CAMs). The proinflammatory lysophospholipid, lysophosphatidic acid (LPA), which is elevated in multiple inflammatory diseases, is a potent activator of the RhoA/Rho kinase signaling pathway and has been shown to induce the expression of CAMs in endothelial cells. The present study was undertaken to map signal transduction downstream of LPA and to investigate the contributions of the Rho kinase isoforms ROCK1 and ROCK2 to adhesion molecule expression in human umbilical vein endothelial cells. LPA activated Rho kinase within minutes and subsequently the NF-kappaB pathway through phosphorylation of the p65 subunit. The lipid also induced the late expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Pharmacologic inhibition of Rho kinase signaling blocked LPA-induced p65 phosphorylation and suppressed ICAM-1 and VCAM-1 expression. Inhibition of the NF-kappaB pathway had no impact on LPA-induced Rho kinase activation, but inhibited adhesion molecule expression. Small interfering RNA-facilitated knockdown of each isoform identified ROCK2 as the mediator of LPA-driven phosphorylation of NF-kappaB p65 and of ICAM-1 and VCAM-1 mRNA and protein induction. Taken collectively, our data are consistent with Rho kinase being upstream of NF-kappaB in driving LPA-mediated adhesion molecule expression. This study also provides the first evidence of the critical involvement of ROCK2 in LPA-induced CAM expression through activation of the NF-kappaB pathway in human endothelial cells.
    Journal of Biological Chemistry 02/2010; 285(17):12536-42. DOI:10.1074/jbc.M109.099630 · 4.57 Impact Factor
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